tbuckley/cabot-search huggingface dataset:
Systemic bevacizumab for aggressive recurrent respiratory papillomatosis: A single center experience of five cases.
Authors: Zengjun Liu, Yang Xiao, Jing Xu, Dongyuan Zhu
Journal: Journal of Clinical Oncology (2022)

e22005 Background: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven benign neoplasm, affecting larynx, trachea, and even lung, leading to voice disorders, airway obstruction, and post-obstructive pneumonia. Currently, there is no curative therapy for RRP.Patients require frequent debulking operations for symptomatic palliation. However, several case reports documented promising results on inhibition of vascular endothelial growth factor (VEGF) by systemic administration of bevacizumab. Methods: We retrospectively analyzed clinical, radiological, and bronchoscopy data of aggressive RRP patients treated with systemic bevacizumab since January 2021. Results: 5 consecutive patients were included. Median age (range) was 8 (4-30), 60% (3/5) were male. The locations of RRP were as follows: localized in the major airway (including vocal cords, larynx, trachea, and main bronchus), n = 1; extensive from major airway to lung parenchyma, n = 4. The median number (range) of local interventions was 8 (2-17) throughout the 12 months prior to bevacizumab treatment. The administration of systemic therapeutic agents, such as HPV vaccine and interferon had been tried in two patients. Bevacizumab was administered at a dose of 5 mg/kg (n = 4) or 7.5 mg/kg (n = 1) intravenously. Treatment intervals were initiated every 2-3 weeks and subsequently extended after achieving the maximum response. The patients received median 6 cycles of bevacizumab (range 4-7). The bevacizumab was given as adjuvant therapy in 2 patients on the 3 rd and 5 th day after laser operation, and as salvage therapy in the other 3 patients. All patients with major airway RRP displayed improvement in disease burden. No patients required surgery during a medain 7 (range 3-8) months follow up periods after initiating bevacizumab treatment. A rapid response was demonstrated in a patient with long-standing extensive pulmonary disease. Except from mild and transit abdominal pain and hemoptysis in 2 patients, systemic treatment with bevacizumab was well tolerated. Conclusions: Inhibition of VEGF by systemic bevacizumab seems to be a well tolerated and effective treatment option for localized and extensive forms of RRP.
Precise assembly of inside-out cell membrane camouflaged nanoparticles via bioorthogonal reactions for improving drug leads capturing
Authors: Xiaolin Zhang, Xueyan Zhen, Yixuan Yang, Quan Feng, Wanqing Yuan, Xiaoyu Xie
Journal: Acta Pharmaceutica Sinica B (2022)

Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function. However, random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites, especially when applied to intracellular regions of transmembrane proteins. Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem. Herein, inside-out cell membrane camouflaged magnetic nanoparticles (IOCMMNPs) were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2. Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe3O4 nanoparticles to prepare IOCMMNPs. The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay. Ultimately, two compounds, senkyunolide A and ligustilidel, were successfully captured, and their potential antiproliferative activities were further testified by pharmacological experiments. It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.
Front- and Rear-driving Patterns of Tumor Thrombus Progression in Clear Cell Renal Cell Carcinoma
Authors: Ruiyang Xie, Huiying Sun, Shuang Zhao, Huang Chen, Weixing Jiang, Xin Dong, Bingqing Shang, Xingang Bi, Yanning Gao, Yu Liu, Jianzhong Shou
Journal: European Urology (2022)
Radiotherapy-immunotherapy related pneumonitis prediction from pre-treatment CT using a deep graph-based integrative model.
Authors: Linlin Yang, Hui Cui, Yanan Duan, Yueyuan Yao, Bing Zou, Linlin Wang
Journal: Journal of Clinical Oncology (2022)

2580 Background: Early prediction of symptomatic pneumonitis (grade ≥ 2) could potentially assist the comprehensive management for non-small cell lung cancer (NSCLC) patients who received radiotherapy combined with immunotherapy. A more accurate integrative model for symptomatic pneumonia prediction using CT images is needed. Methods: This retrospective study contains 243 NSCLC patients (62 symptomatic pneumonitis) who underwent radiotherapy combined with immunotherapy between January 2015 and June 2021. Five-fold cross-validation was performed for training and testing. There were 195 cases in the training set (50 symptomatic pneumonitis) and 48 cases in the validation set (12 symptomatic pneumonitis) in each fold. The deep graph integrative model (DG) was composed of two pre-trained 3D UNet encoders to extract deep features from tumor and lung volumes of pre-treatment CT images, respectively, and a graph attention layer (GAT) for integration and classification. The encoders were fine-tuned using manually segmented tumor and lung CT volumetric patches from the training set. Evaluation measures include area under ROC curve (auc), sensitivity (sen), and specificity (spe). Results: Our new DG achieved auc, sen, and spe of 0.823, 0.767, and 0.810, which outperformed conventional CT radiomics model (auc 0.743, sen 0.620, spe 0.752), 3D UNet based deep radiomics model (auc 0.761, sen 0.746, spe 0.737), and our model without GAT (auc 0.796, sen 0.762, spe 0.782). The improvement was statistically significant (p &lt; 0.001). Conclusions: Our DG model improved symptomatic pneumonia prediction using CT images, which can be used as a tool to effectively improve the safety and personalized treatment of combined radiotherapy with immunotherapy for NSCLC patients.
Effectiveness of complete primary vaccination against COVID-19 at primary care and community level during predominant Delta circulation in Europe: multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021
Authors: Esther Kissling, Mariëtte Hooiveld, Iván Martínez-Baz, Clara Mazagatos, Naoma William, Ana-Maria Vilcu, Marjolein N Kooijman, Maja Ilić, Lisa Domegan, Ausenda Machado, Simon de Lusignan, Mihaela Lazar, Adam Meijer, Mia Brytting, Itziar Casado, Amparo Larrauri, Josephine-L K Murray, Sylvie Behillil, Brechje de Gier, Ivan Mlinarić, Joan O’Donnell, Ana Paula Rodrigues, Ruby Tsang, Olivia Timnea, Marit de Lange, Maximilian Riess, Jesús Castilla, Francisco Pozo, Mark Hamilton, Alessandra Falchi, Mirjam J Knol, Sanja Kurečić Filipović, Linda Dunford, Raquel Guiomar, Jade Cogdale, Carmen Cherciu, Tessa Jansen, Theresa Enkirch, Luca Basile, Jeff Connell, Verónica Gomez, Virginia Sandonis Martín, Sabrina Bacci, Angela MC Rose, Lucia Pastore Celentano, Marta Valenciano
Journal: Eurosurveillance (2022)

Introduction In July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe. Aim Using a multicentre test-negative study, we measured COVID-19 vaccine effectiveness (VE) against symptomatic infection. Methods Individuals with COVID-19 or acute respiratory symptoms at primary care/community level in 10 European countries were tested for SARS-CoV-2. We measured complete primary course overall VE by vaccine brand and by time since vaccination. Results Overall VE was 74% (95% CI: 69–79), 76% (95% CI: 71–80), 63% (95% CI: 48–75) and 63% (95% CI: 16–83) among those aged 30–44, 45–59, 60–74 and ≥ 75 years, respectively. VE among those aged 30–59 years was 78% (95% CI: 75–81), 66% (95% CI: 58–73), 91% (95% CI: 87–94) and 52% (95% CI: 40–61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among people 60 years and older was 67% (95% CI: 52–77), 65% (95% CI: 48–76) and 83% (95% CI: 64–92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30–59 years was 87% (95% CI: 83–89) at 14–29 days and 65% (95% CI: 56–71%) at ≥ 90 days between vaccination and onset of symptoms. Conclusions VE against symptomatic infection with the SARS-CoV-2 Delta variant varied among brands, ranging from 52% to 91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% at 90 days or more between vaccination and onset.
Concurrent <i>TP53</i> mutations and association with outcomes within the <i>SMAD4</i> mutated subgroup of metastatic colorectal cancer.
Authors: Chongkai Wang, Jaideep Singh Sandhu, Amber Tsao, Marwan Fakih
Journal: Journal of Clinical Oncology (2022)

e15578 Background: SMAD4 mutations have been associated with poor prognosis in patients with metastatic colorectal cancer. However, results have been inconsistent between studies. This study aimed to determine the impact of coexisting mutations with SMAD4 on overall survival (OS) in patients with metastatic colorectal cancer. Methods: This is a retrospective, single institute study. Patients with metastatic colorectal cancer treated at City of Hope between 2013 and 2020 and with available Clinical Laboratory Improvement Amendment (CLIA) certified next-generation tumor sequencing (NGS) results were included. Overall survival was measured from the date of diagnosis of metastatic colorectal cancer. Differences in OS between groups were compared using Kaplan–Meier curves, with p-values calculated via log-rank test. Both univariate and multivariate Cox regression models were applied to estimate the hazard ratios and confidence intervals of survival based on mutation status and other clinical factors. Results: 433 patients with metastatic colorectal cancer were identified. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, RAS, BRAF V600E , APC, TP53 and SMAD4 status showed SMAD4 mutation alone was not associated with worse prognosis (multivariate HR = 1.25, 95% CI 0.90-1.73, p = 0.18). We then investigated SMAD4 mutation in combination with each of the top 4 most frequently associated oncogenes or tumor suppressor genes ( TP53-80%, n = 56; APC- 59%, n = 41; RAS-54%, n = 38; BRAF V600E -11%, n = 8) as a predictive biomarker of survival in patients with metastatic colorectal cancer. Coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival (multivariate HR = 2.51, 95% CI 1.46-4.30, p = 0.001). The median overall survival of patients with coexisting SMAD4 and TP53 mutation was 24.2 months compared to 42.2 months for the rest of the population (p = 0.002). Conclusions: SMAD4 mutation status alone is not sufficient for predicting poor prognosis in patients with metastatic colorectal cancer. Coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival in patients with metastatic colorectal cancer.
Does the surgical technique impact the oncologic outcomes after partial nephrectomy? A comparison between open, laparoscopic and robotic approach in a single high-volume tertiary center
Authors: P. Piazza, L. Bianchi, F. Chessa, A. Mottaran, C.V. Pultrone, A. Ercolino, S. Di Fresco, C. Casablanca, M. Droghetti, A. Angiolini, C. Beretta, D. Recenti, A. Bertaccini, C. Roveroni, C. Cacciapuoti, S. Boschi, E. Balestrazzi, P.M. Berrino, S. Puliatti, M. Amato, R. Schiavina, E. Brunocilla
Journal: European Urology (2022)
Acalabrutinib versus rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia: ASCEND results at 4 years of follow-up.
Authors: Wojciech Jurczak, Andrzej Pluta, Malgorzata Wach, Daniel Lysak, Martin Simkovic, Iryna Kriachok, Árpád Illés, Javier De La Serna, Sean Dolan, Philip Campbell, Gerardo Musuraca, Abraham Jacob, Eric Joseph Avery, Jae Hoon Lee, Ganna Usenko, Min Hui Wang, Ting Yu, Paolo Ghia
Journal: Journal of Clinical Oncology (2022)

7538 Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with chronic lymphocytic leukemia (CLL). In the primary analysis of ASCEND (median follow-up 16.1 mo), acala showed superior efficacy with an acceptable tolerability profile vs idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) in pts with relapsed/refractory (R/R) CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). We report the results of the ASCEND study at ~4 years of follow-up. Methods: In this multicenter, randomized, open-label, phase 3 study (NCT02970318), pts with R/R CLL received oral (PO) acala 100 mg BID until progression or unacceptable toxicity or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or unacceptable toxicity; R: 375 mg/m 2 x1 then 500 mg/m 2 IV [8 total infusions]) or BR (B: 70 mg/m 2 IV; R: 375 mg/m 2 x1 then 500 mg/m 2 IV [6 cycles]). Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: A total of 310 pts (acala, n=155; IdR, n=119; BR, n=36) were randomized (median age 67 y; del(17p) 15%, unmutated IGHV 74%, Rai stage 3/4 42%). At median follow-up of 46.5 mo (acala) and 45.3 mo (IdR/BR), acala significantly prolonged INV-assessed PFS vs IdR/BR (median not reached [NR] vs 16.8 mo; P&lt;0.0001); 42-mo PFS rates were 62% for acala vs 19% for IdR/BR. In pts with del(17p), median PFS was NR (acala) vs 13.8 mo (IdR/BR; P&lt;0.0001). In pts with unmutated IGHV, median PFS was NR (acala) vs 16.2 mo (IdR/BR; P&lt;0.0001). Median OS was NR in both arms; 42-mo OS rates were 78% (acala) vs 65% (IdR/BR). ORR was 83% (acala) vs 84% (IdR/BR) (ORR + partial response with lymphocytosis: 92% [acala] vs 88% [IdR/BR]). AEs led to drug discontinuation in 23% of acala, 67% of IdR, and 17% of BR pts. Events of clinical interest (acala vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), and grade ≥3 infections (29% vs 29%). Conclusions: At ~4 years of follow-up, acala maintained efficacy compared with standard-of-care regimens and a consistent tolerability profile in R/R CLL. Clinical trial information: NCT02970318. [Table: see text]
ENLIGHT: Pancancer response prediction to targeted and immunotherapies via tumor transcriptomics.
Authors: Ranit Aharonov, Gal Dinstag, Eldad Shulman, Efrat Elis, Doreen Ben-Zvi, Omer Tirosh, Danh-Tai Hoang, Sanju SInha, Andrea B. Apolo, William L. Dahut, Stan Lipkowitz, Raanan Berger, Razelle Kurzrock, Antonios Papanicolau-Sengos, Fatima Karzai, Padma Sheila Rajagopal, Mark R. Gilbert, Kenneth D. Aldape, Tuvik Beker, Eytan Ruppin
Journal: Journal of Clinical Oncology (2022)

e13556 Background: Precision oncology is gradually advancing into mainstream clinical practice. Despite the significant recent growth in the number of approved biomarkers for immune and targeted therapies, demonstrating significant survival benefits, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We developed ENLIGHT - a transcriptomics-based computational platform that identifies and utilizes clinically relevant genetic interactions (GIs) to predict a patient’s response to cancer treatments. ENLIGHT markedly extends and improves upon SELECT, a previous GI-based framework for obtaining transcriptomics-based response biomarkers. In this study, we focus on three key translational aspects: (i) the number of drugs for which predictions can be obtained (ii) defining a biomarker-based test for Personalized Medicine (PM) that would identify favorable treatments for an individual; and (iii) Improving clinical trial design by excluding a sub-population of patients likely not to respond to the treatment. A key translational feature of the approach is that it does not require training on treatment response data. Thus, in addition to its ability to predict patients' response to approved and well-studied therapies, it can predict the response to new, unexplored treatments. Results: We first tested Enlight in the PM scenario, analyzing 21 patient cohorts from diverse indications, treated with a variety of targeted and immunotherapies. The ENLIGHT treatment matching score is associated with better response with an aggregate Odds Ratio (OR) of 2.59 (95% confidence interval [1.85, 3.55], p= 3.41 e-8). Applied to the WINTHER trial data, encompassing multiple indications and individualized treatments, ENLIGHT recommendations achieved a highly remarkable OR of 11.15 ([2.3, 54.5], p = 8 e-04), demonstrating ENLIGHT’s strong predictive power across a broad spectrum of treatments and cancer types. Second, using ENLIGHT to exclude patients from clinical trials increases the trial response rate, achieving more than 90% of the response rate attainable under an optimal exclusion strategy. Conclusions: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies in translationally oriented, clinical terms, going beyond case-specific biomarkers.
LGG-60. Development and implementation of a complementary diagnostic tool to detect targetable pathways in pediatric glioma patients
Authors: Liana Nobre, Adrian Levine, Scott Milos, Monique Johnson, Benjamin Laxer, Scott Ryall, Robert Siddaway, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract Pediatric Low grade gliomas are mainly driven by MAPK alterations including mutations in BRAF (BRAF fusions and BRAFV600) and FGFR. This has led to the study of BRAF, MEK and more recently FGFR inhibitors resulting in variable responses. We hypothesize that differing levels of RAS_MAPK coupled with alternate pathway activation may be driving this variability. To address this, we designed a custom NanoString assay that integrates proteomic and transcriptomic profiling of 4 key cancer-related, actionable pathways (MAPK, PI3K-AKT-mTOR, JAK-STAT, and NFkB) with robust results on formalin-fixed paraffin embedded tissue, including archival samples up to approximately 15 years old. We validated this assay using 15 gold standard cell lines with defined changes in each pathway including both isogenic activating mutations and perturbation with inhibitors. These findings were confirmed using data from the Cancer Cell Line Encyclopedia. The panel was further validated using a cohort of 40 low grade glioma samples with available RNAseq data where the RNA expression signatures had high concordance between assays. We have currently run the assay on over 200 surgical tumor samples, including 206 gliomas, 15 ependymomas, 11 medulloblastomas, 14 high grade gliomas and 10 control normal brain specimens. Findings indicate significant variability in pathway activations between tumors, although PLGG overall have higher MAPK activation scores than control tissue and other tumor types, a subset of these tumors have increased activity in PIK , JAK and NFKB pathways, underscoring the importance of integrating transcriptomic and proteomic information in precision oncology treatments. Finally, single cell RNA sequencing data from pilocytic astrocytomas demonstrates significant heterogeneity in pathway activation states within the tumor cells, as well as high pathway activations in some tumor associated microglia. This raises further research questions regarding the role of tumor heterogeneity in treatment failures and the impact of targeted therapies on the tumor immune microenvironment.
LINC-22. Primary central nervous system (CNS) germ cell tumors (GCT) in Central America and the Caribbean region: an AHOPCA 20-year experience
Authors: Ana Veronica Giron, Patricia Calderon, Estuardo Pineda, Margarita Montero, Yamel Lizardo, Ute Bartels, Diana S Osorio
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Primary CNS GCT are rare neoplasms in pediatrics. Treatment depends on histological subtype and extent of disease. Overall survival (OS) is above 85% in high-income countries (HIC). OBJECTIVE: To describe the experience in treating CNS GCT in 4 of 8 countries, members of AHOPCA (Asociación de Hemato-Oncología Pediátrica de Centro América) and 5-year OS. DESIGN/METHODS: We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological, clinical characteristics, histology, treatment modalities and outcome were analyzed. RESULTS: From 2001 to 2021, 45 patients were included. Guatemala: 22, Nicaragua: 15, Dominican Republic: 3 and El Salvador: 5. Thirty (66.6%) were male, mean age at diagnosis was 8.6 years (range 12 months to 17 years). Presenting symptoms were headaches/vomiting (n=26, 57.7 %), visual disturbances (n=15, 33.3%), diabetes insipidus (n=7, 15.5%). Two patients (NGGCT) presented with precocious puberty. Upfront surgery was done in 33 cases (73.33%); 21 (63.6%) germinomas, 9 (27.2%) NGGCT and 3 (9%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41mUI/mL) and four NGGCT (BHCG 84.43-201.97mUI/mL or positive AFP&amp;gt;10 ng/mL). Tumor locations included suprasellar (n=15, 33.3%), pineal (n=14, 31.1%), thalamus/basal ganglia (n=5, 11%), other (n=6, 13.3%); and one bifocal. Four (8.8%) had metastatic disease, 6 with positive CSF, staging data was incomplete in 25 patients (55.5%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (61.5% for germinoma and 56% for NGGCT). Two patients with histologically confirmed germinoma relapsed. CONCLUSIONS: Germinoma was the most common histology and there was a male predominance. More than half patients had incomplete staging data and treatment was variable. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging, treatment planning, prevent complications and improve survival.